Recently, a drug delivery system (DDS), whereby a drug is transported selectively toward the cells or tissue in the target part and then the medical effect of the drug is expressed therein without affecting normal cells or tissues, has been discussed in the fields of medicine and pharmacology.
In order to achieve this object, attempts have been made to produce a surface-modified liposome carrying a hydrophilic or fat-soluble drug, on the surface of which a substrate (for example, protein, antigen, antibody, saccharide including polysaccharide) is fixed (e.g., as disclosed in Cancer Res., 43, 5328 (1983); ibid., 47, 4471 (1987); and Liposome Res., 1, 15 (1988-89))
However liposomes are disadvantageous in that they are unstable and thus rapidly disappear in the presence of phagocytes in the reticuloendothelial system or from blood when administered to a living organism. In order to solve these problems, JP-A-63-313724 has disclosed a method for modifying the surface of a liposome with a polysaccharide derivative (the term "JP-A" as used herein means an "unexamined published Japanese patent application").
Furthermore, a number of analytical methods with the use of surface-modified liposomes, which are obtained by fixing physiologically active substances or immunologically active substances including antigens and antibodies on the surface of liposomes, have been disclosed in the fields of clinical research and diagnosis and immunology (e.g., as disclosed in JP-A-61-250558; JP-A-61-66963; and JP-A-60-138466).
Typical examples of methods for modifying the surface of liposomes include a method comprising binding a protein activated with N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP) to N-3-(2-dithiopyridyl) propionyl phosphatidylethanolamine (DTP-PE) (e.g., as disclosed in Nature, 288, 602 (1980)) and another method comprising a cross-linking agent (for example, N-succinimidyl-4-(p-maleimidophenyl) butyrate (SMPB), N-succinimidyl-4-(p-maleimidophenyl)acetate (SMPA), N-succinimidyl-4-(p-maleimidophenyl)propionate (SMPP)) (e.g., as disclosed in J. Biol. Chem., 257, 286 (1982))
Furthermore, other methods for fixing a substrate on the surface of liposomes, have been represented, for example, one comprising preliminarily adding a glycolipid in the preparation of liposomes, then oxidizing the saccharide of the glycolipid to thereby form an aldehyde group and reacting the aldehyde group with an amino group of, for example, a protein to thereby form a Schiff base (refer to Biochim. Biophys. Act., 640, 66 (1981)) and one comprising introducing a hydrophobic group into a substrate, for example, a protein and then integrating it into liposomes which have been separately prepared (e.g., as disclosed in Biochim. Biophys. Act., 812, 116 (1985))
However each of these methods comprises many steps and requires complicated procedures. Thus, there has been a long-standing need in the art to establish a convenient process for easily fixing a substrate on the surface of a liposome to thereby modify the liposome.
In the field of organic synthetic chemistry, on the other hand, a method for efficiently producing an aldehyde by reducing a carboxylic acid derivative with the use of 3-acylthiazolidine-2-thione has been disclosed (e.g., as disclosed in JP-A-54-79275; and Chem. Lett., 1443 (1977)), one selectively producing an amide (e.g., as disclosed in Tetrahedron Lett., 21, 841 (1980); and Hetero cycles, 77, 537 (1982)) and one for producing a thioester (e.g., as disclosed in J. Chem. Research(S), p.20 (1983)). However, there has never been reported hitherto use of 3-acylthiazolidine-2-thione as a reagent for modifying the surface of a liposome.
In the field of polymeric chemistry, furthermore, there has been reported an activator having 2(3H)-benzoxazolone or 2(3H)-benzothiazolone as an eliminating group which selectively forms an amide (e.g., as disclosed in Yuki Gosei Kagaku Kyokai Shi, 48, 144 (1989); Bull. Chem. Soc. Jpn., 58, 3291 (1985); and Macromolecules, 18, 2353 (1985)).